: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of antibodies to DNA (anti-DNA). These antibodies serve as markers of diagnostic and prognostic significance. As a model to elucidate the mechanism of this response, my laboratory has studied the effects of immunization of normal and autoimmune mice with bacterial DNA. This DNA is a potent immunogen because of its content of CpG motifs that stimulate B cell activation and cytokine production. In normal mice, bacterial DNA can induce antibodies specific for the immunizing DNA while in autoimmune NZB/NZW mice, immunization leads to the production of autoantibodies with properties of SLE anti-DNA. In contrast, immunization with mammalian DNA is without effect, suggesting the possibility that this DNA may have inhibitory activities. To analyze further this model, 3 specific aims are proposed: 1) To investigate the genetic basis of induced anti-DNA production through study of a variety of inbred and congenic strains immunized with bacterial DNA, mammalian DNA as well as synthetic oligonucleotides. 2) To investigate the ability of mammalian DNA to inhibit immune responses elicited by bacterial DNA and other immune stimulants in in vitro systems. The effect of synthetic oligonucleotides will also be tested. 3) To assess the role of bacterial DNA-induced nitric oxide and prostaglandin production in antibody and cytokine responses. The role of these mediators and their counter-regulation will be assessed in in vitro systems. Together, these studies will clarify important steps by which foreign and self DNA antigen can modulate the course of autoimmunity.